The present invention in general relates to a method of resolving racemic dimethyl-4,4'-dimethoxy-5,6,5',6'-di(methylenedioxy)biphenyl-2,2'-dicarbox ylate ("DDB") or its analogs.
Antihepatitic drugs include Ara-A, glycyrrhizic acid and the silymaria group. The therapeutic effects of these drugs are not satisfactory. Moreover, some of these medicines are quite expensive. DDB, an intermediate formed in the synthesis of schizandrin C (an ingredient of Fructus schisandrae chinensis), has recently attracted the attention of many researchers in hepatitis therapy. DDB has been clinically proved to possess therapeutic effects in treating hepatitis.
According to the newly promulgated regulations of the U.S. Food and Drug Administration, if a new medicine to be marketed is a racemic isomer mixture, it should be optically resolved into two single phase isomers, and only after the pharmacological, toxicological, safety and clinical reports on the single phase isomers have been submitted can it be put on the market.
Few reports have been directed to the optical resolution of DDB. In J. Org. Chem. 1994, 59, 2577-2580, A. I. Meyers, asymmetric synthesis of (S)-hexamethoxydiphenic acid is reported, in which chiral bromo oxazoline is used in the Ullmann coupling reaction. This process has the disadvantages of process complexity and low yield. Bruce H. Lipshutz also discloses the asymmetric synthesis of (s)-hexamethoxydiphenic acid (Tetrahedron Letters, 1994, 35, 5567-5570). That process is characterized in combining chiral s,s-stilbene diol with two bromophenyl derivatives, followed by an intramolecular biphenyl coupling reaction. It also has the disadvantage of process complexity. Furthermore, the raw material, chiral s,s-stilbene diol, is expensive. Moreover, the process is not easy to control because many organo-metallic reactions and low temperature reactions are involved.
Zhang Chunzhen discloses a method for resolving DDB in which the resolving reagent used is (-)-strychnine, which is a toxic natural occurring substance (Kexue Tongbao, 32 (1), 72, 1987). According to this process, chiral biphenyl dicarboxylic acid is first isolated and then esterified into chiral DDB. The process is also quite complicated.